Secretory lysosome biogenesis in cytotoxic T lymphocytes from normal and Chediak Higashi syndrome patients

The lytic proteins mediating target cell killing are stored in the lysosome s of activated cytotoxic T lymphocytes (CTL) and are secreted upon recognit ion of a target cell. These secretory lysosomes cannot be detected in resti ng T lymphocytes. Interaction of a resting cell with a target cell activate s de novo formation of secretory lysosomes. CTL clones in culture mimic thi s behaviour, and so provide an ideal system for studying secretory lysosome biogenesis and maturation. In the genetic disease, Chediak Higashi syndrom e (CHS), all lysosomes in the cells are enlarged and reduced in number comp ared with wild-type (WT) cells. We have used CTL from this disease to study secretory lysosome biogenesis and maturation. We show that at early stages after activation the secretory lysosomes are identical in WT and mutant ce lls, and that delivery of proteins to the secretory lysosome along the bios ynthetic and endocytic pathways is normal in the mutant cells. With time, t he lysosomes in the mutant cells aggregate, become larger and fewer in numb er and eventually form giant structures. Our results show that the initial steps of secretory lysosome formation are normal in CHS, but that the organ elles subsequently fuse together during cell maturation to form the giant s ecretory lysosomes.